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Towards Routine HPA-screening In Pregnancy to Prevent FNAIT (HIP)

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ClinicalTrials.gov Identifier: NCT04067375
Recruitment Status : Recruiting
First Posted : August 26, 2019
Last Update Posted : August 30, 2019
Sponsor:
Collaborators:
Sanquin Research & Blood Bank Divisions
Landsteiner Foundation for Blood Transfusion
Information provided by (Responsible Party):
DickOepkes, Leiden University Medical Center

Brief Summary:
Fetal and Neonatal Alloimmune Thrombocytopenia (FNAIT) is the most common cause of severe thrombocytopenia in otherwise healthy born neonates. FNAIT results in a risk of bleeding the most severe complication being intracranial haemorraghes (ICH). Bleedings can be prevented by effective antental treatment. In the absence of screening programs this treatment is too late to prevent the first affected child. The investigators aim to identify the pregnancies at risk and describe the incidence and natural course of this disease. In this way fetuses at risk can be identified in the future and timely antenatal treatment can be initiated.

Condition or disease Intervention/treatment
Fetal and Neonatal Alloimmune Thrombocytopenia Other: Clinical data collection.

Detailed Description:

Fetal and Neonatal Alloimmune Thrombocytopenia (FNAIT) is the most common cause of severe thrombocytopenia in neonates. It is an immunological process, in which Human Platelet Antigen (HPA) alloantibodies produced by the mother can cross the placenta and target fetal platelets. The most frequent alloantigen to elicit platelet-reactive antibody responses is HPA-1a. The resulting low platelet count in the fetus or neonate correlates with an increased risk of bleeding complications and severe adverse outcome, defined as perinatal death or intracranial haemorrhage (ICH). This can lead to life-long handicaps, cerebral palsy, cortical blindness and mental retardation. One in 50 pregnancies is at risk for FNAIT, since 2,1% of the Caucasian population is HPA-1a negative. Alloantibodies are calculated to be present in 1:400 pregnancies, leading to FNAIT-related severe adverse outcome in at least 1:1300 fetuses or neonates, and this is likely an underestimation. There is a highly effective antenatal treatment available for preventing these severe adverse outcomes, consisting of weekly injection of intravenous immunoglobulins (IvIG). Unfortunately, in the current practice, this treatment can only be applied in subsequent pregnancies with known alloimmunization, after a symptomatic sibling leading to diagnosis of the disease. In potential future antenatal screening for HPA-alloantibodies, all pregnancies at risk can be identified in time, to start antenatal treatment and reduce severe adverse outcomes. However, before such a program can be realised, detailed information about incidence and natural course of the disease is needed. Furthermore, laboratory tests to identify fetuses at high risk to prevent overtreatment are needed, since approximately 10-30% of the HPA alloimmunized cases result in severe thrombocytopenia and clinically relevant disease.

Objectives:

  1. The main objective of this study is to assess the incidence and severity of FNAIT and bleeding complications (including ICH) among neonates.
  2. To develop a screening platform, including diagnostic assay(s) to identify fetuses at high risk for bleeding complications due to FNAIT.

Study design: Prospective observational cohort

Study population: Pregnant women

Main study parameters/endpoints: The main study parameters are HPA-1a alloantibodies, clinically relevant FNAIT. Secondary parameters include: neonatal outcome (bleeding signs other than ICH, treatment for thrombocytopenia, morbidity).

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: These pregnant women participate in the national antenatal screening programme for Prevention and Screening of Infectious diseases and Erythrocyte Immunisation (PSIE) and have a routine blood sampling at 27th week of gestation. This blood sample will be used this to perform all necessary tests, so no additional (medical) procedures will be performed. Additionally, after delivery clinical data concerning the pregnancy, delivery and the health of the child in the first postnatal period are collected by questioning the obstetric health care provider.

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Study Type : Observational
Estimated Enrollment : 4000 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Towards Routine HPA-screening in Pregnancy to Prevent FNAIT: Assessing Disease Burden and Optimising Risk Group Selection
Actual Study Start Date : March 1, 2017
Estimated Primary Completion Date : April 1, 2020
Estimated Study Completion Date : April 1, 2021

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Pregnant women, HPA-1a positive
RhD or Rhc negative women, identified through prenatal screening for red cell alloimmunization, that are typed as HPA-1a positive.
Other: Clinical data collection.
The following clinical data will be collected; maternal baseline characteristics, delivery related data, neonatal outcome, neonatal bleeding signs.

Pregnant women, HPA-1a negative with HPA-1a alloantibodies
RhD or Rhc negative women, identified through prenatal screening for red cell alloimmunization, that are typed as HPA-1a negative and have formed anti-HPA-1a alloantibodies.
Other: Clinical data collection.
The following clinical data will be collected; maternal baseline characteristics, delivery related data, neonatal outcome, neonatal bleeding signs.

Pregnant women, HPA-1a negative without HPA-1a alloantibodies
RhD or Rhc negative women, identified through prenatal screening for red cell alloimmunization, that are typed as HPA-1a negative and did not have formed anti-HPA-1a alloantibodies.
Other: Clinical data collection.
The following clinical data will be collected; maternal baseline characteristics, delivery related data, neonatal outcome, neonatal bleeding signs.




Primary Outcome Measures :
  1. Clinical relevant FNAIT [ Time Frame: Within 7 days after birth. ]

    Incidence of HPA-1a mediated FNAIT. defined as severe or mild FNAIT

    Severe: Intracranial haemorrhage or Internal organ haemorrhage Mild: petechiae, hematoma, purpura or mucosal bleeding.Thrombocytopenia for platelet transfusion, IVIg or clinical observation.



Secondary Outcome Measures :
  1. Neonatal thrombocytopenia [ Time Frame: Within 7 days after birth. ]
    Thrombocytopenia: platelet count <150 x10^9/L Moderate thrombocytopenia: platelet count <100 x10^9/L Severe thrombocytopenia: platelet count <50 x10^9/L Extremely severe thrombocytopenia: platelet count <20 x10^9/L

  2. Neonatal infection [ Time Frame: Within 7 days after birth. ]
    CRP >10 and positive blood culture, for which antibiotics are administerd

  3. Chromosomal abnormality [ Time Frame: Within 7 days after birth. ]
    Chromosomal abnormalities as measured by DNA assessment (karyotyping, array, WGS/WES)


Other Outcome Measures:
  1. Maternal age [ Time Frame: Measured at 27 weeks gestational age of current pregnancy. ]
    Maternal age in years

  2. Number of participatnts with idiopathic thrombocytopenic purpura [ Time Frame: At inclusion ]
    Idiopathic thrombocytopenic purpura defined as thrombocytopenia in presence of autoantibodies.

  3. Spontaneous miscarriage in obstetric history [ Time Frame: At inclusion ]
    Number of previous spontaneous miscarriage before 12 weeks' gestation

  4. Intrauterine fetal demise in obstetric history [ Time Frame: At inclusion ]
    Number of previous IUFD after 12 weeks' gestation

  5. Number of participants with hypertensive disorder [ Time Frame: 3 months after delivery ]
    Pre-eclamspsia or pregnancy induced hypertension

  6. Prematurity [ Time Frame: through study completion, until delivery, an average of 6 months ]
    Gestational age at delivery below 37 weeks (premature) Or below 34 weeks gestation (very premature)

  7. Apgar Score at 5 minutes after birth [ Time Frame: 5 minutes after birth ]
    Measured as Apgar Score below 7 at 5 minutes after birth

  8. Small for gestational age [ Time Frame: through study completion, until delivery, an average of 6 months ]
    Birth weight (in grams) below the 10th percentile for the corresponding estational age at delivery


Biospecimen Retention:   Samples With DNA

Via a nationwide routine screening during pregnancy EDTA anticoagulated blood samples will be collected. Plasma and buffy coat will be stored.

On plasma the following analysis will be performed:

  • HPA-1a typing by a new developed protol making use of ELISA.
  • Antibody screening by the Luminex assay.
  • Surface Plasmon Resonance on a sensor chip.

To identify high risk cases fucosylation level of the antibodies will be performed. In addition to this the binding and functional effects to endothelial cells will be assessed.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Pregnant women.
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Pregnant women.
Criteria

Inclusion Criteria:

  • All pregnant women, of whom routine blood samples are taken at 27 weeks gestational age (GA).

Exclusion Criteria:

  • There are no predefined exclusion criteria, since we are aiming to determine the incidence in the complete pregnant population in the Netherlands.

[ WILSONBEKWAAM EXCLUSIE]


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04067375


Contacts
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Contact: Dian Winkelhorst, MD +31715262896 D.Winkelhorst@sanquin.nl
Contact: Thijs de Vos, MD +31715262824 T.W.de_Vos@lumc.nl

Locations
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Netherlands
Stichting Bloedbank Sanquin Recruiting
Amsterdam, Netherlands, 1066 CX
Contact: Dian Winkelhorst, MD    +31618806369    D.Winkelhorst@sanquin.nl   
Contact: Thijs de Vos, MD    +31652665280    T.W.de_Vos@lumc.nl   
Sponsors and Collaborators
Leiden University Medical Center
Sanquin Research & Blood Bank Divisions
Landsteiner Foundation for Blood Transfusion
Investigators
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Study Director: Dick Oepkes, Prof MD PhD Department of Obstetrics, Leiden University Medical Centre, Leiden
Study Director: Masja de Haas, Prof MD PhD Department of Immunohematology Diagnostics, Sanquin Diagnostics, Amsterdam
Study Director: Ellen vd Schoot, Prof MD PhD Department of Experimental Immunohematology, Sanquin Reseach, Amsterdam
Study Data/Documents: Information website  This link exits the ClinicalTrials.gov site
Information for participating caregivers, participants or other interested parties.
Informed Consent Form  This link exits the ClinicalTrials.gov site
Digital form
Informed Consent Form  This link exits the ClinicalTrials.gov site
Paper form

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Responsible Party: DickOepkes, Professor of Obstetrics and Fetal Therapy. Head of the section Fetal Medicine., Leiden University Medical Center
ClinicalTrials.gov Identifier: NCT04067375    
Other Study ID Numbers: P16.002
First Posted: August 26, 2019    Key Record Dates
Last Update Posted: August 30, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No information will be given about individual participant data to the participating pregnant women, nor the obstetric caregiver will be informed about the serological HPA-1a typing results. Also, we decided to perform the antibody detection test after birth. Thus no additional information can be known that would otherwise change the management of the current pregnancy, according to the Dutch Guidelines.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Thrombocytopenia
Thrombocytopenia, Neonatal Alloimmune
Blood Platelet Disorders
Hematologic Diseases
Infant, Newborn, Diseases